Fungicidal 3-phenyl-5-(substituted methyl)isoxazoles

ABSTRACT

A class of isoxazoles having a phenyl or substituted-phenyl group at the 3-position and a substituted-methyl group at the 5-position are useful for the control of fungal foliar phytopathogens.

This is a division of application Ser. No. 695,669, filed June 14, 1976,and issued Aug. 22, 1978, as U.S. Pat. No. 4,109,002.

BACKGROUND OF THE INVENTION

This invention relates to the field of agricultural chemistry andprovides new plant protective fungicides.

The control of harmful microorganisms has long been a major concern ofchemical research. In particular, the control of fungal foliarphytopathogens was one of the first goals of agricultural chemistry, andresearch in the field continues at a high pitch.

SUMMARY OF THE INVENTION

The present invention provides a new method of reducing the adverseeffects of fungal foliar phytopathogens which comprises contacting thephytopathogens on the foliage of plants with an effective amount of acompound of the formula ##STR1## wherein R represents

chloro,

bromo,

fluoro,

trifluoromethyl, or

hydrogen;

R¹ represents

bromo,

chloro,

isothiocyanato,

amino,

amino hydrochloride or hydrobromide,

--NHCSNH(C₁ -C₃ alkyl),

--NHCO₂ (C₁ -C₃ alkyl), or

3,5,7-triaza-1-azoniaadamantyl chloride or bromide.

In a preferred embodiment, the invention is particularly useful for thecontrol of grape downy mildew. Fungicidal compositions are provided.

DESCRIPTION OF THE PREFERRED EMBODIMENT

In the above generic formula, the term C₁ -C₃ alkyl refers to methyl,ethyl, propyl and isopropyl.

Particular classes of compounds which are contemplated as particularlyefficacious in the method of this invention include the classes ofcompounds wherein:

1. R represents chloro, bromo, fluoro or trifluoromethyl;

2. R represents trifluoromethyl;

3. R represents chloro, bromo or fluoro;

4. R represents hydrogen;

5. R¹ represents isothiocyanato, amino, amino hydrochloride orhydrobromide, NHCSNH(C₁ -C₃ alkyl), NHCO₂ (C₁ -C₃ alkyl) or3,5,7-triaza-1-azoniaadamantyl chloride or bromide;

6. R¹ represents bromo or chloro;

7. R¹ represents NHCSNH(C₁ -C₃ alkyl) or NHCO₂ (C₁ -C₃ alkyl);

8. R¹ represents bromo, chloro, isothiocyanato, amino, hydrochloride orhydrobromide, NHCSNH(C₁ -C₃ alkyl) or NHCO₂ (C₁ -C₃ alkyl);

9. R¹ represents isothiocyanato, amino, amino hydrochloride orhydrobromide, NHCSNH(C₁ -C₃ alkyl) or NHCO₂ (C₁ -C₃ alkyl);

10. R¹ represents isothiocyanato;

11. R and R¹ are as described by subparagraphs 1 and 5 above;

12. R and R¹ are as described by subparagraphs 1 and 6 above;

13. R and R¹ are as described by subparagraphs 1 and 7 above;

14. R and R¹ are as described by subparagraphs 1 and 8 above;

15. R and R¹ are as described by subparagraphs 1 and 9 above;

16. R and R¹ are as described by subparagraphs 1 and 10 above;

17. R and R¹ are as described by subparagraphs 2 and 5 above;

18. R and R¹ are as described by subparagraphs 2 and 6 above;

19. R and R¹ are as described by subparagraphs 2 and 7 above;

20. R and R¹ are as described by subparagraphs 2 and 8 above;

21. R and R¹ are as described by subparagraphs 2 and 9 above;

22. R and R¹ are as described by subparagraphs 2 and 10 above;

23. R and R¹ are as described by subparagraphs 3 and 5 above;

24. R and R¹ are as described by subparagraphs 3 and 6 above;

25. R and R¹ are as described by subparagraphs 3 and 7 above;

26. R and R¹ are as described by subparagraphs 3 and 8 above;

27. R and R¹ are as described by subparagraphs 3 and 9 above;

28. R and R¹ are as described by subparagraphs 3 and 10 above;

29. R and R¹ are as described by subparagraphs 4 and 5 above;

30. R and R¹ are as described by subparagraphs 4 and 6 above;

31. R and R¹ are as described by subparagraphs 4 and 7 above;

32. R and R¹ are as described by subparagraphs 4 and 8 above;

33. R and R¹ are as described by subparagraphs 4 and 9 above;

34. R and R¹ are as described by subparagraphs 4 and 10 above.

Throughout this document, all percentages, ratios and proportions are inweight units. All temperatures are on the Celsius scale.

The following typical compounds of this invention are mentioned toassure that agricultural chemists understand the invention. Thecompounds are exemplary of the invention but should not be interpretedas bounding the limits of it.

5-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole

5-bromomethyl-3-(4-fluorophenyl)isoxazole

3-(4-fluorophenyl)-5-isothiocyanatomethylisoxazole

5-aminomethyl-3-(4-bromophenyl)isoxazole

5-aminomethyl-3-(4-chlorophenyl)isoxazole

5-aminomethyl-3-phenylisoxazole, hydrobromide

5-aminomethyl-3-phenylisoxazole

5-aminomethyl-3-(4-chlorophenyl)isoxazole, hydrochloride

1-methyl-3-[[3-(4-fluorophenyl)-5-isoxazolyl]methyl]-2-thiourea

1-ethyl-3-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-2-thiourea

1-isopropyl-3-[[3-(4-bromophenyl)-5-isoxazolyl]methyl]-2-thiourea

1-propyl-3-[(3-phenyl-5-isoxazolyl)methyl]-2-thiourea

[[3-(4-trifluoromethylphenyl)-5-isoxazolyl]methyl]carbamic acid, methylester

[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]carbamic acid, ethyl ester

[(3-phenyl-5-isoxazolyl)methyl]carbamic acid, isopropyl ester

[(3-phenyl-5-isoxazolyl)methyl]carbamic acid, propyl ester

1-[[3-(4-trifluoromethylphenyl)-5-isoxazolyl]methyl]-3,5,7-triaza-1-azoniaadamantanechloride

1-[[3-(4-bromophenyl)-5-isoxazolyl]methyl]-3,5,7-triaza-1-azoniaadamantanechloride

1-[[3-(4-fluorophenyl)-5-isoxazolyl]methyl]-3,5,7-triaza-1-azoniaadamantanebromide

The preferred compounds of this invention are5-bromomethyl-3-phenylisoxazole,5-bromomethyl-3-(4-chlorophenyl)isoxazole,5-aminomethyl-3-(4-chlorophenyl)isoxazole,5-isothiocyanatomethyl-3-phenylisoxazole, and1-methyl-3-[(3-phenyl-5-isoxazolyl)methyl]-2-thiourea.

The compounds of this invention are prepared by processes which arepresently known to organic chemists, and which start from readilyobtainable starting compounds. The preparation of all of the compoundsbegins with an appropriately substituted benzaldehyde, which is firstreacted with hydroxylamine to form the corresponding aldehyde oxime. Thehydroxylamine may be used in the form of a hydrohalide salt, in whichcase an acid scavenger, such as a tertiary amine, an alkali metalalkoxide, or an inorganic base such as sodium carbonate, sodiumbicarbonate, potassium hydroxide and the like should be used in thereaction. The preferred solvent is an aqueous alkanol, but othersolvents, such as diethyl ether, chloroform and the like are alsosatisfactory. The preferred reaction temperature is the refluxtemperature of the reaction mixture.

The α-carbon of the aldehyde oxime is chlorinated, most easily by simplecontact with free chlorine in chloroform. Low temperatures from about 0°to about 10° are preferred. The chlorinated oximes are the precursors ofall the compounds of this invention. They are unstable in the pure formand are used without purification, although they may be isolated in theimpure form.

The isoxazole ring of the compounds is formed by the reaction of thechlorinated oxime with a propargyl halide to form the isoxazole compoundhaving the corresponding 3-phenyl substituent and a 5-halomethyl group.Such compounds are used in the invention, and are also used asintermediates for the preparation of other compounds. The ring closurestep is performed at low temperatures in the range of 0° to 15° in thepresence of a strong base, preferably triethylamine. The preferredreaction solvent is diethyl ether, although other typical inert reactionsolvents may be used, such as tetrahydrofuran, benzene, alkanes and thelike. Other bases besides triethylamine may be used, such as pyridine,sodium hydroxide, alkali metal alkoxides, lithium carbonate and thelike.

A halomethyl compound is reacted with hexamethylenetetramine to form thetriaza-1-azoniaadamantane compounds. The reaction is preferably carriedout in chloroform at reflux temperature. Other solvents, such as diethylether, alkanes and benzene may be used at temperatures in the range offrom 25° to 60°.

The aminomethyl salts are prepared by simple hydrolysis of thecorresponding triazaadamantane compound with concentrated hydrochloricor hydrobromic acid at temperatures in the range of from roomtemperature to the reflux temperature, although reflux temperature ismost convenient and preferred. An alkanol solvent is preferred. Thesalts may be neutralized with bases to prepare the free aminomethylcompounds.

The isothiocyanato compounds are readily prepared by reacting anaminomethyl compound with thiophosgene in the presence of a strong base,such as pyridine, triethylamine, sodium hydroxide, alkali metal alkoxideand the like. Reaction solvents such as chloroform, tetrahydrofuran anddimethylformamide at temperatures from about 0° to 10° are appropriate.

The thioureas are prepared by reacting an aminomethyl compound with analkylisothiocyanate, as at reflux temperature in a solvent such as ethylacetate, and the carbamic acid esters are prepared by reacting anaminomethyl compound with an alkylhaloformate, preferably attemperatures from about 0° to about 10° in the presence of a strong baseas described above.

While the above general discussion, combined with the general knowledgeof the art, is sufficient to enable an organic chemist to prepare anycompound of this invention, the following specific preparative examplesare supplied to assist the reader.

All of the compounds discussed below were identified by nuclear magneticresonance analysis, infrared analysis, mass spectroscopy and elementalmicroanalysis procedures as was appropriate in each individual case.

The first examples below illustrate the closure of the isoxazole ring toform 5-halomethyl compounds.

EXAMPLE 1 5-bromomethyl-3-phenylisoxazole

A 121 g. portion of benzaldoxime was dissolved in 2 l. of chloroform andthe solution was cooled to 5°. Dry gaseous chlorine was bubbled in,keeping the temperature of the mixture below 20°, until the solutionturned first blue and then yellow. The solvent was then removed undervacuum at a temperature below 40°, and the residue was taken up in about1.5 l. of diethyl ether and washed first with 500 ml. of 4 percentsodium hydroxide solution and then with 500 ml. of ice water. Theorganic solution was dried by filtering through sodium sulfate, andcooled below 5° C. A 120 g. portion of propargyl bromide was added andthe mixture was stirred overnight and allowed to warm to roomtemperature. The reaction mixture was then treated with activated carbonand filtered. The filtrate was concentrated to about 400 ml., and theproduct was separated by the addition of petroleum ether. Two crops ofcrystals were obtained, giving a total of 117 g. of5-bromomethyl-3-phenylisoxazole, m.p. 87°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            50.45%         50.71%                                            H            3.39           3.51                                              N            5.88           5.91                                              O            6.72           6.93                                              ______________________________________                                    

EXAMPLE 2 5-bromomethyl-3-(4-chlorophenyl)isoxazole

The procedure of Example 1 was followed, starting with 156 g. of4-chlorobenzaldoxime and 180 g. of propargyl bromide to produce 178 g.of product, m.p. 116°-117°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            44.07%         44.31%                                            H            2.59           2.41                                              N            5.14           5.24                                              O            5.87           5.58                                              ______________________________________                                    

EXAMPLE 3 5-bromomethyl-3-(4-trifluoromethylphenyl)isoxazole

The same process was followed, starting with 51 g. of4-trifluoromethylbenzaldoxime and 55 g. of propargyl bromide to produce52 g. of product, m.p. 83°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            43.17%         43.22%                                            H            2.31           2.32                                              N            4.58           4.81                                              ______________________________________                                    

The following two examples illustrate the preparation of thetriaza-1-azoniaadamantyl compounds.

EXAMPLE 41-[(3-phenyl-5-isoxazolyl)methyl]-3,5,7-triaza-1-azoniaadamantanebromide

A 90 g. portion of the product of Example 1 was dissolved in 1.5 l. ofchloroform and 70 g. of hexamethylenetetramine was added. The mixturewas stirred at reflux temperature for 4 hours, and was filtered hot. Thesolids were dried under vacuum to obtain 143 g. of impure product, m.p.159°-160°, which contained about 93 percent product and 7 percenthexamethylenetetramine.

EXAMPLE 51-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-3,5,7-triaza-1-azoniaadamantanebromide

The process above was followed, starting with 149 g. of the product ofExample 2 and 100 g. of hexamethylenetetramine to produce 224 g. of thedesired product, m.p. 188°-189°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            46.79%         46.99%                                            H            4.17           4.57                                              N            17.05          17.31                                             O            3.90           3.64                                              ______________________________________                                    

Aminomethyl compounds are prepared as shown in the following series ofexamples.

EXAMPLE 6 5-aminomethyl-3-(4-chlorophenyl)isoxazole

A 205 g. portion of the product of Example 5 was dissolved in 1.5 l. ofmethanol and 250 ml. of concentrated hydrochloric acid was added. Themixture was stirred at reflux temperature overnight, and the solvent wasthen evaporated under vacuum. The residue was neutralized with aqueoussodium hydroxide and the product was extracted from the aqueous mixturewith methylene dichloride and was purified by evaporating the solventand recrystallizing the residue from ethanol-petroleum ether. Theproduct was 78 g. of 5-aminomethyl-3-(4-chlorophenyl)isoxazole, m.p.81°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            57.57%         57.35%                                            H            4.35           4.35                                              N            13.43          13.65                                             O            7.67           7.47                                              ______________________________________                                    

EXAMPLE 7 5-aminomethyl-3-(4-trifluoromethylphenyl)isoxazole

The process of Examples 4 and 6 was followed, starting with 20 g. of theproduct of Example 3 and 30 g. of hexamethylenetetramine to prepare 22g. of the corresponding triaza-1-azoniaadamantane compound, which wasreacted with 50 ml. of hydrochloric acid in methanol and neutralized toobtain 8.8 g. of the desired product, m.p. 59°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            54.55%         54.63%                                            H            3.75           3.45                                              N            11.57          11.49                                             ______________________________________                                    

EXAMPLE 8 5-aminomethyl-3-phenylisoxazole

A 10 g. portion of the product of Example 4 was reacted withhydrochloric acid as above to obtain 1.1 g. of the desired product, m.p.50°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            68.95%         68.95% -H 5.79 5.78                               N            16.08          15.86                                             O            9.18           9.17                                              ______________________________________                                    

EXAMPLE 9 5-aminomethyl-3-phenylisoxazole, hydrochloride

A 2.4 g. portion of the product of Example 1 was reacted with 1.4 g. ofhexamethylenetetramine in 25 ml. of ethanol in the presence of 2 g. ofsodium iodide. The reaction mixture was stirred at reflux temperatureuntil thin-layer chromatography indicated that the starting compound hadall reacted. After the mixture was cooled, gaseous hydrogen chloride wasbubbled in for 15 minutes, and the reaction mixture was dumped into alarge amount of water. The aqueous mixture was washed with methylenedichloride, neutralized with 2 N sodium hydroxide, and extracted withadditional methylene dichloride. The organic layer was evaporated todryness under vacuum, and the residue was extracted with 1 Nhydrochloric acid. The acid layer was washed with methylene dichlorideand was then neutralized with sodium carbonate. The product wasextracted from the neutral solution with chloroform. The solvent wasevaporated under vacuum and the residue was recrystallized from hotchloroform and identified as 700 mg. of5-amino-methyl-3-phenylisoxazole, hydrochloride, m.p. 222°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            57.01%         57.18%                                            H            5.26           5.44                                              N            13.30          13.29                                             O            7.59           7.68                                              ______________________________________                                    

Synthesis of a typical isothiocyanato compound is illustrated by thefollowing example.

EXAMPLE 10 5-isothiocyanatomethyl-3-phenylisoxazole

A 7 g. portion of the product of Example 8 was dissolved in 100 ml. ofchloroform and cooled to ice bath temperature. Ten g. of thiophosgene in15 ml. of chloroform and 23 g. of sodium carbonate in 150 ml. of waterwere added simultaneously. The mixture was stirred for 1 hour, and theorganic layer was then separated. The water layer was extracted withchloroform, and the organic layers were combined, dried and evaporatedto dryness under vacuum. The residue was taken up in diethyl ether andtreated with activated carbon. After filtration, the ether solution wasconcentrated to about 75 ml. and about 250 ml. of petroleum ether wasadded, oiling out the product. Chromatography over a silica gel columnpurified the product, which was recrystallized from petroleum ether toproduce 3.2 g. of 5-isothiocyanatomethyl-3-phenylisoxazole, m.p. 66°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            61.04%         60.79%                                            H            3.73           3.56                                              N            12.95          12.84                                             O            7.40           7.45                                              ______________________________________                                    

EXAMPLE 11 3-(4-chlorophenyl)-5-isothiocyanatomethylisoxazole

A 7 g. sample of the product of Example 6 was reacted according to thescheme of Example 10 with 10 g. of thiophosgene to produce 2.4 g. of thedesired product, m.p. 74°-76°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            52.69%         52.84%                                            H            2.79           3.10                                              N            11.18          11.20                                             Cl           14.17          14.46                                             ______________________________________                                    

The examples immediately below illustrate the synthesis of thioureacompounds.

EXAMPLE 12 1-methyl-3-[(3-phenyl-5-isoxazolyl)methyl]-thiourea

A 7 g. portion of the product of Example 8 was dissolved in 200 ml. ofethyl acetate and 15 ml. of methyl isothiocyanate was added. Thereaction mixture was stirred at reflux temperature for 3 hours, and wasthen evaporated to dryness under vacuum. The residue was taken up inethyl acetate, treated with activated carbon and recrystallized byaddition of petroleum ether. Further purification by chromatography overalumina gel was used, eluting impurities with chloroform and theneluting the product with 25 percent methanol-75 percent chloroform. Theproduct-containing fractions were concentrated under vacuum, and theproduct was recrystallized from ethyl acetate-petroleum ether to produce5 g. of 1-methyl-3-[(3-phenyl-5-isoxazolyl)methyl]-2-thiourea, m.p.118°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            58.28%         58.20%                                            H            5.30           5.32                                              N            16.99          17.12                                             ______________________________________                                    

EXAMPLE 131-methyl-3-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-2-thiourea

The process above was repeated, starting with 8 g. of the product ofExample 6 and 15 ml. of methylisothiocyanate to produce 4.6 g. of thedesired product, m.p. 135°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            51.15%         51.45%                                            H            4.29           4.08                                              N            14.91          15.17                                             O            5.68           5.70                                              ______________________________________                                    

The final two examples demonstrate the synthesis of carbamic acid estersof this invention.

EXAMPLE 14 [(3-phenyl-5-isoxazolyl)methyl]carbamic acid, ethyl ester

A 7 g. portion of the product of Example 8 was dissolved in 50 ml. ofpyridine, cooled in an ice bath, and combined with 10 ml. of ethylchloroformate. The mixture was stirred at ice bath temperature for 1hour and allowed to warm to room temperature while being stirred for 2hours more. The mixture was then poured into ice water and the crudeproduct was separated by filtration and purified by chromatography oversilica gel with ethyl acetate as the eluent. The yield was 6 g. ofpurified [(3-phenyl-5-isoxazolyl)-methyl]carbamic acid, ethyl ester,m.p. 82°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            63.40%         63.48%                                            H            5.73           5.66                                              N            11.38          11.31                                             O            19.49          18.74                                             ______________________________________                                    

EXAMPLE 15 [[3-(4-chlorophenyl)-5-isoxazolyl]methyl]carbamic acid, ethylester

The process above was followed, starting with 8 g. of the product ofExample 6 and 15 ml. of ethyl chloroformate to produce 3.7 g. of thedesired product, m.p. 137°.

    ______________________________________                                                   Theoretical  Found                                                 ______________________________________                                        C            55.62%         55.81%                                            H            4.67           4.40                                              N            9.98           10.03                                             O            17.10          16.92                                             ______________________________________                                    

The compounds of this invention have been tested to evaluate theirability to protect plants from the adverse effects of fungal foliarphytopathogens. The following examples illustrate the tests employed andthe results produced by representative compounds.

In most of the tests, each compound was formulated for testing bydissolving or suspending about 3.5 weight percent of it in 50:50acetone:ethanol containing about 10 g./100 ml of a nonionic surfactant.The solution was then dispersed in deionized water in a quantity suchthat the water dispersion contained the various compond concentrationsindicated in the specific test methods and the table below.Concentrations are measured in parts per million, by weight (ppm).

In most of the tests, the compound dispersions were applied to the testplants by spraying them with an air atomizer, using sufficientdispersion to wet the plants thoroughly. Other methods of formulationand application were used in a few tests, as described in the specifictest methods which follow.

Untreated, infected controls and untreated, normal controls wereincluded in each test. The results are reported on a 1-5 rating scalewhere 1 indicates severe disease and 5 indicates complete control of thedisease. An empty space in the table below shows that the indicatedcompound was not tested at the indicated rate. In some cases, more thanone test was performed against a given phytopathogen, and the results insuch cases are reported as averages. Compounds are identified by theexample numbers used above.

Test 1 late blight of tomato

Four-week-old tomato seedlings were sprayed with aqueous dispersionscontaining test compounds at compound concentrations indicated in thetable below. The following day, the foilage was inoculated with anaqueous suspension of propagules of Phytophthora infestans. The inoculumhad been reared on infected wheat seed. The plants were held for twodays in a moist chamber, and were then transferred to the greenhouse.The plants were observed and rated for disease control about one weekafter application of the test compounds.

Test 2 powdery mildew of beam

The host plants were 10-day-old bean seedlings. After aqueousdispersions containing test compounds at compound concentrationsindicated in the table below had been sprayed on the foilage of thebeans and allowed to dry, the plants were placed in the greenhouse andinoculated by storing them under other bean plants which were heavilyinfected with powdery mildew (Erysiphe polygoni). After about 10 days,the plants were observed and the results recorded as usual.

Test 3 anthracnose of cucumber

Aqueous dispersions containing test compounds at compound concentrationsindicated in the table below were applied to healthy cucumber seedlingsgrown in sterilized greenhouse soil. The following day, the plants wereinoculated with Colletotrichum lagenarium conidia as an aqueoussuspension. The fungus had been grown on potato dextrose agar in petridishes. The plants were held in a moist chamber for two days andtransferred to the greenhouse, and the disease was observed and ratedapproximately 12 days after application of the test compounds.

Test 4 rice blast of rice

The test compound dispersions, at compound concentrations indicated inthe table below, were applied to healthy rice seedlings growing thicklyin plastic pots. The plants were inoculated on the next day withPiricularia oryzae (grown on rice polish agar) and the plants were heldin a moist chamber for two days. The plants were then held in thegreenhouse for 5-7 days and observed.

Test 5 helminthosporium leaf spot of wheat

Healthy wheat seed was planted in sterile greenhouse soil. When theseedlings were 4-5 inches tall, they were sprayed with test compounddispersions at compound concentrations indicated in the table below. Theday after treatment, the plants were inoculated with a spore suspensionof Helminthosporium sativum which had been grown on potato dextroseagar. The plants were placed in a moist growth chamber for two days tostart disease growth, and were then transferred to the greenhouse. Abouta week after treatment, the plants were observed and the results wererecorded.

Test 6 botrytis of grape

Sound grape berries were sterilized by immersion in diluted sodiumhypochlorite and thoroughly rinsed. The berries were placed on wirescreen shelves in compartmented Pyrex plates. The berries were thenflamed and sprayed with test chemical dispersions. The following day,the berries were inoculated by spraying 5 ml. of a conidial suspensionof Botrytis cinerea over each plate containing 12 berries. The inoculumhad been grown on frozen lima bean agar. A small amount of water wasadded to each plate and a cover was sealed over each plate. After 48hours at 25°, the berries were observed and disease ratings recorded.

Test 7 apple scab of apple

Apple seedlings at the 4-6 leaf stage were sprayed with aqueousdispersions of the test compounds. The following day, the plants weresprayed with a suspension of fresh conidia of Venturia inaequalisobtained from infected apple seedlings kept as a source of inoculum. Theplants were held for two days in a 20° moist chamber to start diseasegrowth and were then transferred to the greenhouse. About two weeksafter application of the compounds, the plants were observed and theresults were recorded.

Test 8 downy mildew of grape

Young expanding grape leaves were detached from healthy vines on the dayof the test. Leaves were placed individually in plastic petri dishes,bottom side up, on top of an expanded plastic mat. Water was added toeach petri dish, and the petiole of each leaf was wrapped with awater-soaked wad of cotton. Each leaf was sprayed with an aqueousdispersion of the compound to be tested.

After the test compound dispersions had dried, the leaves wereinoculated by atomizing a conidial suspension of Plasmopara viticola(grown on infected leaf tissue) evenly over the leaf surface. The plateswere then covered and were stored in a growth room at about 18° and 100%relative humidity where they were exposed to 8 hours a day of artificiallight. After about a week of storage, all the leaves were observed andthe signs of disease were evaluated.

Test 9 cercospora leaf spot of sugar beet

Sugar beet seedlings were transplanted into square plastic pots andallowed to grow for three weeks. Aqueous dispersions containing 400 ppm.of the compounds to be tested were sprayed on the leaf surfaces. Afterthe dispersions dried, but within 24 hours, the plants were inoculatedwith a conidial suspension of Cercospora beticola which had been grownon sugar beet leaf decoction agar. After the plants were held in a moistchamber for two days, they were transferred to the greenhouse andobserved 2-3 weeks later.

    __________________________________________________________________________    Compound                                                                      of    Appln.                                                                  Example                                                                             Rate                                                                              Late                                                                              Powdery                                                                            Anthrac-                                                                           Rice                                                                             Helmintho- Apple                                                                             Downy                                                                              Cercos-                        No.   ppm.                                                                              Blight                                                                            Mildew                                                                             nose Blast                                                                            sporium                                                                             Botrytis                                                                           Scab                                                                              Mildew                                                                             pora                           __________________________________________________________________________    1     400 3   1    2    2  1     1    5   5    1                                    100                             4   3                                         80  1        1    1                                                           25                              4   1                                         6                               1                                       2     400 1   4    1    2  1     1    1   5    2                                    100     1                                1                                    25      1                                1                              3     400     1    1    1  1     1        5    1                              4     400 1   1    2    1  1     1    1        1                              5     400 1   1    2    1  1     1    1   1    1                                    100          1                                                                25           1                                                          6     400 1   1    4    1                 4    3                              7     400 1   1    1    1                 5    1                              8     400 1   1    1    2  1     1    1        1                              9     400 1   1    1    1  1     1    4   1    1                                    100                             1                                             25                              1                                       10    400 1   1    1    2  1     1    4        1                                    100                             4                                             25                              4                                             6                               1                                       12    400 1   1    2    3  1     1    1   3    3                                    100          1    3                                                           25           1    1                                                     14    400 1   1    1    1  1     3    1   1    4                                    100                                      1                                    25                                       1                              __________________________________________________________________________

Many of the compounds have been retested in replicated special testsagainst downy mildew and botrytis rot of grape. The test methods werethe same as those described above, except that multiple replicates wereused at the various rates. In many cases, the tests reported below havebeen repeated several times, and the results thereof have been averaged.

    ______________________________________                                                     Appln.                                                           Compound of  Rate      Downy                                                  Example No.  ppm.      Mildew     Botrytis                                    ______________________________________                                        1            800       5          1                                                        400       5          1                                                        200       4          1                                                        100       3                                                                    50       2                                                                    25       2                                                      2            800       4          1                                                        400       5          1                                                        200       5          1                                           4            800       5          1                                                        400       4          1                                                        200       2          1                                           5            800       4                                                                   400       5                                                                   200       3                                                      6            800       4          1                                                        400       4          1                                                        200       4          1                                           7            800       3          1                                                        400       4          1                                                        200       1          1                                           8            800       1          1                                                        400       3          1                                                        200       3          1                                                        100       3          1                                           9            800       4          1                                                        400       3          1                                                        200       2          1                                           10           800                  5                                                        400       5          4                                                        200       4          3                                                        100       4          2                                                         50       3          1                                                         25       3          1                                           12           800       4          1                                                        400       1          1                                                        200       2          1                                                        100       1                                                      13           800       4          1                                                        400       4          1                                                        200       3          1                                           14           800       1          1                                                        400       4          1                                                        200       3          1                                           15           800       3          1                                                        400       1          1                                                        200       3          1                                           ______________________________________                                    

It is notable that the compounds of this invention can be used againstother harmful pathogens, as well as against fungal foliarphytopathogens. For example, the following results were obtained whenrepresenative compounds were tested in a system to determine theirability to inhibit the growth of microorganisms in vitro. The organismsnamed below were grown in culture media, appropriate for the growh ofthe various organisms, containing the compounds at variousconcentrations, measured in micrograms/milliliter. The table below liststhe lowest concentration at which each compound inhibited the growth ofthe indicated microorganism.

A. Staphylococcus aureus

B. Streptococcus faecalis

C. Proteus morganii

D. Salmonella typhosa

E. Klebsiella pneumoniae

F. Enterobacter aerogenes

G. Serratia marcescens

H. Escherichia coli

I. Citrobacter freundii

J. Pseudomonas aeruginosa

K. Bordetella bronchiseptica

L. Salmonella typhimurium

M. Pseudomonas solanacearum

N. Erwinia amylovora

O. Candida tropicalis

P. Trichophyton mentagrophytes

Q. Aspergillus flavus

R. Ceratocystis ulmi

S. Pasteurella multocida (bovine)

T. Pasteurella multocida (avian)

U. Salmonella dublin

V. Pseudomonas sp.

W. Mycoplasma gallisepticum

X. Mycoplasma hyorhinis

Y. Mycoplasma hyopneumcniae

Z. Aeromonas liquefaciens

    __________________________________________________________________________    Cmp.                                                                          of                                                                            Ex.                                                                           No. A    B  C  D  E  F  G  H  I  J  K    L  M                                 __________________________________________________________________________    1   100     100                     100                                       2   <10     100                     <10                                       3   <10                                                                       4   100  100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100                                                                              100  100                                                                              100                               5   100  100                                                                              100                                                                              100                                                                              100         100                                                                              100                                                                              100  100                                                                              100                               6   100           100               100                                       7   100           100               100                                       10  <10  100                                                                              100                                                                              100         100                                                                              100   75   100                                                                              100                               12  100                                                                       13  <10                             100                                       14                                                                            __________________________________________________________________________    Cmp.                                                                          of                                                                            Ex.                                                                           No.    N  O    P    Q    R    S T U V W X Y Z                                 __________________________________________________________________________    1         100  <10  100  <10                                                  2         <10  <10  <10  <10                                                  3         100  100  100  100                                                  4      100                                                                              100  100            50                                                                              50                                                                              50                                                                              50                                                                              25                                                                              50                                                                              50                                  5      100                                                                              100                                                                 6         100  100       100                                                  7      100                                                                              100  100                                                            10     100                                                                              <10  <10  100  <10  12                                                                              25                                                                              12                                                                              25                                                                              50                                                                              50                                                                              50                                  12                                                                            12                       100                                                  14        100                                                                 __________________________________________________________________________

Several of the compounds have also been found to be effective againstaquatic weeds. For example, the compounds of Examples 1, 3 and 10 areeffective against coontail, Ceratophyllum demersum L., hydrilla,Hydrilla verticillata, and duckweed, Lemna minor L., at concentrationsof 10 ppm. or less.

The test data reported above show that the compounds of this inventionare useful for the protection of plants from the adverse effects of avariety of fungal foliar phytopathogens. Accordingly, the invention is anew method of reducing the adverse effects of fungal foliarphytopathogens which comprises contacting the phytopathogens on thefoliage of host plants with an effective phytopathogen-inhibiting amountof one of the compounds described above. The method is carried out byapplying a compound of the invention to the plants to be protected.

A preferred aspect of the invention is its use to protect grape plantsfrom downy mildew, which disease is caused by the phytopathogenPlasmopara viticola. The invention is used against downy mildewaccording to the general teachings below which describe use of theinvention against phytopathogens in general.

Practice of the method does not necessarily kill the phytopathogens. Asthe data above show, application of a phytopathogen-inhibiting amount ofa compound reduces the adverse effects of the disease, even though onlya part of the phytopathogen population may be killed by the compound.The term "phytopathogen-inhibiting amount" is used here to describe anamount which is sufficient to reduce the adverse effects of aphytopathogen. The term "reducing the adverse effects" refers toweakening the pathogen sufficiently that its reproduction rate and itsvigor are decreased, with the result that the express signs of thedisease, and the concomitant injury to the host plant, are decreased ascompared with phytopathogens growing on untreated plants.

As is usual in the plant protection art, best results are obtained byapplying the compound several times during the growing season atintervals of from one to a few weeks, depending on the weather and theseverity of the disease.

The methods of formulating the compounds and preparing dispersions ofthe formulations, and the methods of applying dispersions of thecompounds to the plants to be protected, are entirely conventional inthe plant protection art. Some explanation of the methods of applicationwill be given merely to assure that those skilled in the art can carryout the invention without undue experimentation.

It is usual in describing foliar applications of plant protectants tomeasure the application rate by the concentration of the dispersion inwhich it is applied. The application rate is measured in this waybecause it is customary to apply a sufficient amount of the dispersionto cover the foliage with a thin film. The amount of dispersion appliedis thus dependent on the foliar area of the plants being treated, andthe quantity of plant protecting compound is dependent upon itsconcentration in the dispersion. In general, compound concentrations inthe range of from about 50 to about 1500 parts of compound per millionparts by weight of dispersion are used in the practice of thisinvention.

The compounds of this invention are usually applied in the form offungicidal compositions which are important embodiments of theinvention. Such compositions comprise a compound of this invention and aphytologically-acceptable inert carrier, and frequently are concentratedformulations which are dispersed in water for application, or are dustformulations. The compositions are prepared according to procedures andformulae which are conventional in the agricultural chemical art, butwhich are novel and important because of the presence therein of thecompounds of this invention. Some description of the formulation of thefungicidal compositions will be given, to assure that agriculturalchemists can readily prepare any desired fungicidal composition.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-suspendible or emulsifiable formulationsare either solids usually known as wettable powders or liquids usuallyknown as emulsifiable concentrates. Wettable powders comprise anintimate mixture of the active compound, an inert carrier andsurfactants. The concentration of the active compound is usually fromabout 10 percent to about 90 percent by weight. The inert carrier isusually chosen from among the attapulgite clays, the montmorilloniteclays, the diatomaceous earths, or the purified silicates. Effectivesurfactants, comprising from about 0.5 percent to about 10 percent ofthe wettable powder, are found among the sulfonated lignins, thecondensed naphthalenesulfonates, the naphthalenesulfonates, thealkylbenzenesulfonates, the alkyl sulfates, and nonionic surfactantssuch as ethylene oxide adducts of alkyl phenol.

Typical emulsifiable concentrates of the compounds comprise a convenientconcentration of the compound, such as from about 100 to about 500 g.per liter of liquid, dissolved in an inert carrier which is a mixture ofwater-immiscible organic solvent and emulsifiers. Useful organicsolvents include the aromatics, especially the xylenes, and thepetroleum fractions, expecially the high-boiling naphthalenic andolefinic portions of petroleum such as heavy aromatic naphtha. Otherorganic solvents may also be used, such as terpenic solvents includingrosin derivatives, and complex alcohols such as 2-ethoxyethanol.Suitable emulsifiers for emulsifiable concentrates are chosen from thesame types of surfactants used for wettable powders.

Adjuvants are frequently used to improve the ability of the aqueousdispersion to coat and adhere to foliage. Such adjuvants as gums,emulsified polybutenes, cationic surfactants and lignin derivatives canoften increase the potency of the method in a specific use.

Less frequently, the compounds are applied to foliage in the form ofdusts. Agricultural chemical dusts typically comprise the compound in afinely powdered form, dispersed in a powdered inert carrier. Most often,the carrier is a powdered clay, such as pyrophyllite, bentonite, avolcanic deposit, or montmorillonite. Dusts are usually prepared tocontain concentrations of the compound at the highest part of theconcentration range, such as 1500 ppm., and may contain even more activeingredient.

Dispersions of the compounds are applied in the usual manners.Low-pressure sprayers, high-pressure sprayers and low-volume air blastequipment are all effective for the application of water-dispersedcompounds of the invention. Dust dispersions are readily applied bymeans of the usual equipment which blows the dust into intimate contactwith the foliage.

We claim:
 1. A fungicidal method of reducing the adverse effects offungal foliar phytopathogens which comprises applying to thephytopathogens on the foliage of host plants an effectivephytopathogen-inhibiting amount of a compound of the formula ##STR2##wherein R representschloro, bromo, fluoro, trifluoromethyl, or hydrogen;R¹ representsbromo or chloro.
 2. A method of claim 1 wherein thephytopathogen is Plasmopara viticola and the host plants are grapes. 3.A method of claim 1 wherein the amount of the compound is from about 50to about 1,500 ppm.
 4. A method of claim 2 wherein the amount of thecompound is from about 50 to about 1,500 ppm.
 5. The method of claim 1wherein the compound is 5-bromomethyl-3-phenylisoxazole.
 6. The methodof claim 1 wherein the compound is5-bromomethyl-3-(4-chlorophenyl)isoxazole.